Gender differences in adult traumatic brain injury according to the Glasgow coma scale: A multicenter descriptive study.

PURPOSE: Patients' gender, which can be one of the most important determinants of traumatic brain injury (TBI) outcomes, is also likely to interact with many other outcome variables of TBI. This multicenter descriptive study investigated gender differences in epidemiological, clinical, treatment, mortality, and variable characteristics in adult TBI patients. METHODS: The selection criteria were defined as patients who had been diagnosed with TBI and were admitted to the hospital between January 1, 2016 and December 31, 2018. A total of 4468 adult TBI patients were enrolled at eight University Hospitals. Based on the list of enrolled patients, the medical records of the patients were reviewed and they were registered online at each hospital. The registered patients were classified into three groups according to the Glasgow coma scale (GCS) score: mild (13-15), moderate (9-12), and severe (3-8), and the differences between men and women in each group were investigated. The risk factors of moderated and severe TBI compared to mild TBI were also investigated. RESULTS: The study included 3075 men and 1393 women and the proportion of total males was 68.8%. Among all the TBI patients, there were significant differences between men and women in age, past history, and GCS score. While the mild and severe TBI groups showed significant differences in age, past history, and clinical symptoms, the moderate TBI group showed significant differences in age, past history, cause of justice, and diagnosis. CONCLUSION: To the best of our knowledge, this multicenter study is the first to focus on gender differences of adult patients with TBI in Korea. This study shows significant differences between men and women in many aspects of adult TBI. Therefore, gender differences should be strongly considered in TBI studies.

Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition.

Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to ¼100 µM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.

Cranial nerve outcomes after primary stereotactic radiosurgery for symptomatic skull base meningiomas.

OBJECTIVE: To evaluate cranial nerve (CN) outcomes after primary stereotactic radiosurgery (SRS) for petroclival, cavernous sinus, and cerebellopontine angle meningiomas. METHODS: From our prospectively maintained database of 2022 meningioma patients who underwent Leksell stereotactic radiosurgery (SRS) during a 30-year interval, we found 98 patients with petroclival, 242 with cavernous sinus, and 55 patients with cerebellopontine angle meningiomas. Primary radiosurgery was performed in 245 patients. Patients included in this report had at least one CN deficit at the time of initial presentation and a minimum of 12 month follow up. Median age at the time of SRS was 58 years. Median follow up was 58 months (range 12-300 months), Median tumor volume treated with SRS was 5.9 cm3 (range 0.5-37.5 cm3), and median margin dose was 13 Gy (range 9-20Gy). RESULTS: Tumor control was achieved in 229 patients (93.5%) at a median follow up of 58 months. Progression free survival rate (PFS) after SRS was 98.7% at 1 year, 96.4% at 3 years, 93.7% at 5 years, and 86.4% at 10 years Overall, 114 of the 245 patients (46.5%) reported improvement of CN function. Patients with CP angle meningiomas demonstrated lower rates of CN improvement compared to petroclival and cavernous sinus meningioma patients. Deterioration of CN function after SRS developed in 24 patients (10%). The rate of deterioration was 2.8% at 1 year, 5.2% at 3 years, and 8% at 10 years. CONCLUSION: Primary SRS provides effective tumor control and favorable rate of improvement of preexisting CN deficit.

Factors Associated with Clinical Outcomes in Patients with Primary Intraventricular Hemorrhage.

BACKGROUND Primary intraventricular hemorrhage (PIVH) is an uncommon type of intracerebral hemorrhage. Owing to its rarity, the clinical and radiological factors affecting outcomes in patients with PIVH have not been widely studied. MATERIAL AND METHODS We retrospectively reviewed 112 patients (mean age 53 years) treated for PIVH at our institution from January 2004 to December 2014. Clinical and radiological parameters were analyzed 3 months after initial presentation to identify factors associated with clinical outcomes, as assessed by the Glasgow Outcome Scale (favorable ≥4, unfavorable <4). RESULTS Of the 99 patients who underwent angiography, causative vascular abnormalities were found in 46%, and included Moyamoya disease, arteriovenous malformation, and cerebral aneurysm. At 3 months after initial presentation, 64% and 36% of patients were in the favorable and unfavorable outcome groups, respectively. The mortality rate was 19%. However, most survivors had no or mild deficits. Age, initial Glasgow Coma Scale (GCS) score, simplified acute physiology score (SAPS II), modified Graeb score, and various radiological parameters reflecting ventricular dilatation were significantly different between the groups. Specifically, a GCS score of less than 13 (p=0.015), a SAPS II score of less than 33 (p=0.039), and a dilated fourth ventricle (p=0.043) were demonstrated to be independent predictors of an unfavorable clinical outcome. CONCLUSIONS In this study we reveal independent predictors of poor outcome in primary intraventricular hemorrhage patients, and show that nearly half of the patients in our study had predisposing vascular abnormalities. Routine angiography is recommended in the evaluation of PIVH to identify potentially treatable etiologies, which may enhance long-term prognosis.

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma.

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-L-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells' ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival.

Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

Romo1 is associated with ROS production and cellular growth in human gliomas.

Romo1 is a mitochondrial protein whose elevated expression is commonly observed in various types of human cancers. However, the expression status of Romo1 and its implication in the pathogenesis of human glioblastoma (GBM) remain largely undefined. To understand the role of Romo1 in the progression of GBM, we explored its expression in a series of GBM tissues and cell lines and determined its effect on ROS production, cell proliferation, and tumor growth. Romo1 was frequently overexpressed at the mRNA level in both primary tumors and cell lines and its elevation was more commonly observed in high grade tumors versus low grade tumors. Romo1 expression was associated with ROS production and its knockdown led to a marked reduction of in vitro cellular growth and anchorage-independent growth of GBM. Consistently, Romo1 depletion induced a G2/M arrest of the cell cycle that was accompanied with accumulation of phospho-cdc2. Furthermore, a mouse xenograft assay revealed that Romo1 depletion significantly decreased tumor formation and growth. Therefore, our data demonstrate that Romo1 upregulation is a common event in human GBMs and contributes to the malignant tumor progression, suggesting that Romo1 could be a new therapeutic target for human GBM.

Prognostic Factors of Clinical Outcomes in Patients with Spontaneous Thalamic Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a well-known condition, but ICH restricted to the thalamus is less widely studied. We investigated the prognostic factors of thalamic ICHs. MATERIAL AND METHODS: Seventy patients from January 2009 to November 2014 were retrospectively reviewed. Patients who demonstrated spontaneous ICH primarily affecting the thalamus on initial brain computed tomography (CT) were enrolled. Patients were categorized into 2 groups based on their Glasgow Outcome Scale (GOS) scores. Various presumptive prognostic factors were analyzed to investigate relationships between various clinical characteristics and outcomes. RESULTS: Of the enrolled patients, 39 showed a GOS of 4-5, and were categorized as the good outcome group, while another 31 patients showed a GOS of 1-3 and were categorized as the poor outcome group. Initial GCS score, calculated volume of hematoma, presence of intraventricular hemorrhage (IVH), coexisting complications, hydrocephalus, performance of external ventricular drainage, and modified Graeb's scores of patients with IVH were significantly different between the 2 groups. In multivariate analysis, among the factors above, initial GCS score (P=0.002, Odds ratio [OR]=1.761, Confidence interval [CI]=1.223-2.536) and the existence of systemic complications (P=0.015, OR=0.059, CI=0.006-0.573) were independently associated with clinical outcomes. Calculated hematoma volume showed a borderline relationship with outcomes (P=0.079, OR=0.920, CI=0.839-1.010). CONCLUSIONS: Initial GCS score and the existence of systemic complications were strong predictive factors for prognosis of thalamic ICH. Calculated hematoma volume also had predictive value for clinical outcomes.

Risk factors of delayed surgical evacuation for initially nonoperative acute subdural hematomas following mild head injury.

BACKGROUND: Although the majority of patients with minimal acute subdural hematomas (aSDHs) can be managed conservatively, some require delayed aSDH evacuation due to hematoma enlargement. This study was designed to determine the risk factors associated with delayed hematoma enlargement leading to surgery in patients with aSDHs who did not initially require surgical intervention. METHODS: From 2002 to 2012, 98 patients were treated for nonoperative aSDHs following mild head injury (Glasgow Coma Scale scores of 13-15). The outcome variables were radiographic evidence of SDH enlargement on serially obtained computed tomography (CT) images and later surgical evacuation. Univariate and multivariate analyses were applied to both the demographic and initial radiographic features to identify risk factors for SDH progression and surgery. RESULTS: Overall, 64 patients (65 %) revealed minimal SDH or spontaneous hematoma resolution (conservative group) with conservative management at their last follow-up CT scan. The remaining 34 patients (35 %) received delayed hematoma evacuation (delayed surgery group) a median of 17 days after the head trauma. There were no significant differences between the two groups for baseline characteristics, including age, injury type, degree of brain atrophy, prior history of antithrombotic drugs, and coagulopathy. The presence of cerebral contusions and subarachnoid hemorrhages was more common in the conservative group (p = 0.003 and p = 0.003, respectively). On multivariate analysis, hematoma volume (p = 0.01, odds ratio [OR] = 1.094, 95 % confidence interval [CI] = 1.021-1.173) and degree of midline shift (p = 0.01, OR = 1.433, 95 % CI = 1.088-1.888) on the initial CT scan were independently associated with delayed hematoma evacuation. CONCLUSIONS: A critical proportion of patients with minimal aSDHs occurring after mild head injury can progress over several weeks and require hematoma evacuation. Especially patients with a large initial SDH volume and accompanying midline shift require careful monitoring of hematoma progression.

Primary Intracranial Ewing Sarcoma With an Unusual Presentation: A Case Report.

Primary extraosseous intracranial Ewing sarcoma (ES) is an extremely rare disease, limited to the pediatric population, that primarily originates in the skull. Here, we present an unusual case of adult Ewing's sarcoma originating from the brain parenchyma. The 50-year-old male patient visited our hospital with severe headache lasting 3 weeks. MRI presented 6.1×6.2×5.2 cm sized heterogeneously enhanced mass containing peritumoral edema in the right frontal lobe. The patient underwent right frontal craniotomy, at which time the gray and red masses adhered to the surrounding brain parenchyma. The mass was completely resected using neuronavigation and electrophysiological monitoring. Histopathological examination revealed ES-compatible findings of small round cell tumor and CD-99 positive membranous immunostaining. Next generation sequencing revealed translocation and fusion of EWSR1 and FLI1, consistent with a confirmed diagnosis of ES. Consequently, the patient underwent postoperative radiotherapy. The present case revealed adult primary intracranial ES arising from the frontal lobe. Although its etiology remains poorly understood, intraparenchymal ES should be included in the differential diagnosis of parenchymal brain tumors.

Corrigendum: Clinical feasibility of miniaturized Lissajous scanning confocal laser endomicroscopy for indocyanine green-enhanced brain tumor diagnosis.

[This corrects the article DOI: 10.3389/fonc.2022.994054.].

A prospective multicenter assessor blinded pilot study using confocal laser endomicroscopy for intraoperative brain tumor diagnosis.

In this multi-center, assessor-blinded pilot study, the diagnostic efficacy of cCeLL-Ex vivo, a second-generation confocal laser endomicroscopy (CLE), was compared against the gold standard frozen section analysis for intraoperative brain tumor diagnosis. The study was conducted across three tertiary medical institutions in the Republic of Korea. Biopsy samples from newly diagnosed brain tumor patients were categorized based on location and divided for permanent section analysis, frozen section analysis, and cCeLL-Ex vivo imaging. Of the 74 samples from 55 patients, the majority were from the tumor core (74.3%). cCeLL-Ex vivo exhibited a relatively higher diagnostic accuracy (89.2%) than frozen section analysis (86.5%), with both methods showing a sensitivity of 92.2%. cCeLL-Ex vivo also demonstrated higher specificity (70% vs. 50%), positive predictive value (PPV) (95.2% vs. 92.2%), and negative predictive value (NPV) (58.3% vs. 50%). Furthermore, the time from sample preparation to diagnosis was notably shorter with cCeLL-Ex vivo (13 min 17 s) compared to frozen section analysis (28 min 28 s) (p-value < 0.005). These findings underscore cCeLL-Ex vivo's potential as a supplementary tool for intraoperative brain tumor diagnosis, with future studies anticipated to further validate its clinical utility.

Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas.

We evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3­11.6). The marginal tumor dose (median= 15 Gy, range 12­25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12­185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy.

The significance of decompressive craniectomy for older patients with traumatic brain injury: a propensity score matching analysis from large multi-center data.

The efficacy of decompressive craniectomy (DC) for traumatic brain injury (TBI) have been investigated in two recent randomized clinical trials (RCTs) and DC is recommended as an optional treatment for improving overall survival compared to medical treatment. However, the two RCTs enrolled extremely young adults, and the efficacy of DC in older adults remains questionable. Therefore, to identify the efficacy of DC in older adults, we compared patients who received medical care with those who underwent DC after propensity score matching (PSM). From the Korea Multi-center Traumatic Brain Injury Database, 443 patients identified as having intracranial hypertension and a necessity of DC were retrospectively enrolled. The patients were classified into the DC (n = 375) and non-DC (n = 68) groups according to operation records. The PSM was conducted to match the patients in the DC group with those receiving medical care (non-DC). After PSM, the newly matched group (DC, n = 126) was compared with patients without DC (non-DC, n = 63). The mean difference in the logit of the propensity scores (LPS) was 0.00391 and the mean age of enrolled patients were 65 years. The results of the comparative analyses after PSM showed that the 6-month mortality rate of the non-DC group was higher than that of the DC group (61.9% vs. 51.6%, p = 0.179). In terms of favorable outcomes (modified Rankin Scale [mRS] score < 4), the DC group showed a lower rate of favorable mRS scores (11.9% vs. 17.5%, p = 0.296) than the non-DC group.

Recurrence of Rathke's Cleft Cyst Following Surgery and Histopathological Considerations for Recurrence: A Case Presentation.

Recurrence of Rathke's cleft cysts (RCC) following surgery is not uncommon. We present a 33-year-old male patient with chronic headache and visual disturbances whose MRI showed mostly cystic, suprasellar mass with peripheral enhancement. Endoscopic extended transsphenoidal approach and tumor resection was performed and RCC was pathologically confirmed postoperatively. Early recurrence was first suspected at 3 months following surgery, and his serial MRIs showed a recurred mass without associated clinical symptoms. Upon further histopathological study, extensive squamous metaplasia and high Ki-67 were seen. Also, in this study, we discuss important factors associated with cyst recurrence following surgery.

Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations.

BACKGROUND AND PURPOSE: The purpose of this study was to define the risk of rebleeding after stereotactic radiosurgery (SRS) for hemorrhagic arteriovenous malformations with or without associated intracranial aneurysms. METHODS: Between 1987 and 2006, we performed Gamma Knife SRS on 996 patients with brain arteriovenous malformations; 407 patients had sustained an arteriovenous malformation hemorrhage. Sixty-four patients (16%) underwent prior embolization and 84 (21%) underwent prior surgical resection. The median target volume was 2.3 mL (range, 0.1-20.7 mL). The median margin dose was 20 Gy (range, 13.5-27 Gy). RESULTS: The overall rate of total obliteration defined by angiography or MRI was 56%, 77%, 80%, and 82% at 3, 4, 5, and 10 years, respectively. Before obliteration, 33 patients (8%) sustained an additional hemorrhage after SRS. The overall annual hemorrhage rate until obliteration after SRS was 1.3%. The presence of a patent aneurysm was significantly associated with an increased rehemorrhage risk after SRS (annual hemorrhage rate, 6.4%) compared with patients with a clipped or embolized aneurysm (annual hemorrhage rate, 0.8%; P=0.033). CONCLUSIONS: When an aneurysm is identified in patients with arteriovenous malformations selected for SRS, additional endovascular or surgical strategies should be considered to reduce the risk of bleeding during the latency interval.

Gamma knife radiosurgery for clinically persistent acromegaly.

Gamma knife radiosurgery (GKRS) is an important additional strategy for unresected clinically active pituitary adenomas. Radiosurgery for acromegaly aims to achieve tumor growth control and endocrine remission, potentially obviating the need for lifetime medication suppression therapy. Forty patients with clinically active acromegaly underwent GKRS between 1988 and 2009. Thirty-four patients had undergone prior surgical resection. The median follow-up interval was 72 months (range 24-145). Endocrine remission was defined as growth hormones (GH) level <2.5 ng/ml and a normal insulin-like growth factor 1 (IGF-1) level (age and sex adjusted) off growth hormone inhibiting drugs for at least 3 months. Endocrine control was defined as normal GH and IGF-1 levels on suppression medication. Endocrine remission was achieved in 19 (47.5 %) patients and endocrine control in four additional (10.0 %) patients. Patients with lower IGF-1 level and with tumors that were less invasive of the cavernous sinus before GKRS were associated with better GH remission rates. Imaging-defined local tumor control was achieved in 39 (97.5 %) patients (27 had tumor regression). One patient with delayed tumor progression underwent a second GKRS procedure. Three other patients had repeat GKRS because of persistently elevated and clinically symptomatic GH and IGF-1 levels. Sixteen (40.0 %) patients eventually developed a new pituitary axis deficiency at a median onset of 36 months after radiosurgery. No patient developed new visual dysfunction. Gamma knife radiosurgery, which is most often applied in clinically symptomatic acromegaly persistent after initial microsurgery, was most effective when the tumor was less invasive of the cavernous sinus and when patients had lower IGF-1 levels before GKRS. Almost one half of the patients no longer required long term medication suppression.

Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study.

We evaluated the efficacy and safety of gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumab combined with chemotherapy in 11 patients with recurrent glioblastoma multiforme who experienced tumor progression despite aggressive initial multi-modality treatment. Our experience included eight male and three female patients. The median patient age at GKSR was 62 years (range 46-72 years). At the time of GKSR, seven patients had a first recurrence and four had two or more recurrences. The median interval from the initial diagnosis until GKSR was 17 months (range 5-34.5 months). The median tumor volume was 13.6 cm(3) (range 1.2-45.1 cm(3)) and the median margin dose of GKSR was 16 Gy (range 13-18 Gy). Following GKSR, bevacizumab was administrated with irinotecan in nine patients and with temozolomide in one patient. One patient was treated with bevacizumab monotherapy. The treatment outcomes were compared to 44 case-matched controls who underwent GKSR without additional bevacizumab. At a median of 13.7 months (range 4.6-28.3 months) after radiosurgery, tumor progression was evident in seven patients. The median progression-free survival (PFS) was 15 months (95% confidential interval (CI), 6.5-23.3 months). Six-month and 1-year PFS rates were 73 and 55%, respectively. The median overall survival (OS) from GKSR was 18 months (95% CI, 10.1-25.7 months) and 1-year OS rate was 73%. One patient (9%) experienced grade III toxicity and one patient (9%) had major adverse radiation effects. Compared with patients who did not receive bevacizumab, the patients who received bevacizumab had significantly prolonged PFS (15 months vs. 7 months, P = 0.035) and OS (18 months vs. 12 months, P = 0.005), and were less likely to develop an adverse radiation effect (9 vs. 46%, P = 0.037). The combination of salvage GKSR followed by bevacizumab added potential benefit and little additional risk in a small group of patients with progressive glioblastoma. Further experience is needed to define the efficacy and long-term toxicity with this strategy.